title: Total gastrectomy may result in reduced drug effectiveness due to an increase in the expression of the drug-metabolizing enzyme Cytochrome P450, in the liver.
abstract: In patients with gastrectomy, it is possible that drug effectiveness is reduced compared to healthy subjects due to the increased of the drug-metabolizing enzyme, Cytochrome P450 (CYP). The purpose of this study is to verify this possibility. Gastrectomy model mice were prepared to evaluate the expression level of various CYPs in the liver from 2 to 24 weeks post-operation. No significant differences were observed in the protein expression levels of CYP3A, CYP1A, CYP2C, and CYP2D between the sham operation group and the gastrectomy group up to 4 weeks after the gastrectomy. On the other hand, significant increases in the protein expression levels of any CYPs were observed in the gastrectomy group compared to the sham operation group from 12 weeks after the gastrectomy onward. These increases in expression levels were maintained until 24 weeks after the gastrectomy. The examination of metabolic activity in the liver in the gastrectomy group using triazolam revealed that the metabolic activity at 12 weeks after the gastrectomy was significantly increased in the gastrectomy group. The administration of the anticancer drug imatinib, which is a substrate of CYP3A, to mice at 12weeks after gastrectomy resulted in an increase in the metabolic rate, suggesting a possible decrease in drug effectiveness. It has been revealed that drug effectiveness may be reduced after gastrectomy because the expression levels of various CYPs in the liver were increased over a prolonged period. The results of this study can serve as valuable fundamental knowledge for drug therapy in patients with gastrectomy.
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ishii
authors.forename: Takahiro
authors.initials: T
authors.lastname: Toda
authors.forename: Nobutomo
authors.initials: N
authors.lastname: Ikarashi
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kusunoki
authors.forename: Risako
authors.initials: R
authors.lastname: Kon
authors.forename: Wataru
authors.initials: W
authors.lastname: Ochiai
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Machida
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Sugiyama
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001481:Basal Metabolism / Q000187:drug effects / Q000502:physiology; D001549:Benzamides / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004435:Eating / Q000187:drug effects / Q000502:physiology; D005743:Gastrectomy / Q000009:adverse effects*; D000068877:Imatinib Mesylate; D007420:Intestine, Large / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D007421:Intestine, Small / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D014229:Triazolam / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D014229:Triazolam; D000068877:Imatinib Mesylate; D003577:Cytochrome P-450 Enzyme System
keywords: Cytochrome P450; Gastrectomy; Imatinib